Fused ring systems containing (1 3)oxazine

ABSTRACT

FUSED RING SYSTEMS CONTAINING (1,3) OXAZINE OF FORMULA I AND THE METHOD FOR THEIR PREPARATION HAVE BEEN DISCLOSED.   2,3-(-X-)(-R1),4-R3,5,6-(-Z-)(-R2)-2,3-DIHYDRO-   4H-1,3-OXAZINE   X REPRESENTS 1,2,3,4-TETRAHYDROISOQUINOLINE, 1,2,3,4,-TETRAHYDRO-2-CARBOLINE, TETRAHYDRO-4-PHTHALAZINONE, 1,2DIHYDROQUINAZOLINE, HEXAHYDROPYRIMIDINE; Z IS AN AROMATIC OR HETEROAROMATIC NUCLEUS, R1, R2 AND R3 ARE HYDROGEN OR VARIOUS SUBSTITUENTS. THE COMPOUNDS OF THIS INVENTION ARE HYPOTENSIVE AGENTS.

United States Patent O Ser. No. 32,358

Int. Cl. C07d 87/20, 99/02 US. Cl. 260-244 R 11 Claims ABSTRACT OF THEDISCLOSURE Fused ring systems containing [1,3]oxazine of Formula I andthe method for their preparation have been disclosed.

X represents 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydro 2carboline, tetrahydro 4 phthalazinone, 1,2- dihydroquinazoline,hexahydropyrimidine; Z is an aromatic or heteroaromatic nucleus, R R andR are hydrogen or various substituents. The compounds of this inventionare hypotensive agents.

This application for US. Letters Patent is a continuation-in-part ofcopending application U.S. Ser. No. 673,927, filed Oct. 9, 1967, nowabandoned.

The present invention relates to a new class of fused ring systemscontaining [1,3]oxazines of Formula I and the method for theirpreparation.

X represents 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydro 2carboline, tetrahydro 4 phthalazinone, 1,2- dihydroquinazoline, andhexahydropyrimidine; Z is benzene, naphthalene, phenanthrene, pyridine,quinoline, isoquinoline, indole, carbazole; R and R are hydrogen, loweralkyl, aryl lower alkyl, aryl, amino, lower alkylamino, aralkylamino,hydroxy, lower alkoxy, methylenedioxy, halogen, carbo lower alkoxy,carboxy, dilower alkylaminocarbanyl, dilower alkylamino lower alkyl; Ris hydrogen, lower alkyl or lower alkyl, aryl.

In the above definitions for R R and R and X and Z, lower alkyl and thelower alkyl portion of lower alkoxy is meant to include from 1 to 6carbon atoms, such as methyl, ethyl, propyl, isopropyl, and the like;halogen is meant to include all four members of its family, i.e.,bromine, fluorine, iodine, and chlorine.

This invention also includes within its scope a novel method for thepreparations of these compounds.

The compounds of this invention are hypotensive agents. They are usefulin the treatment of mild hypertension in mammals, such as dogs, cats,monkeys and the like. They are administered orally or parenterally,preferably intravenously, at a dose of 1 to 10 mg. per kilogram bodyweight of the mammal several times daily in order to produce the desiredhypotensive effects. This, for a mammal weighing about 70 kg., a dose of70 to 700 mg. several times daily is recommended.

3,649,626 Patented Mar. 14, 1972 The compounds of this invention may beformulated with standard pharmaceutical carriers, such as water,lactose, mannitol, starch and the like, to form dosage forms such astablets, capsules, suspensions, and the like. They may also beformulated with liquid vehicles, such as water or saline, to give dosageforms suitable for intravenous or intramuscular injections.

The above compounds are prepared by heating a phenolic Mannich base ofFormula II,

B5 (II) wherein R and R are lower alkyl or lower alkyl aryl, or R and Rtaken together with the nitrogen atom to which they are attached forma'morpholine, pyrrolidine, piperazine or piper-idine ring, in dioxane atreflux temperature with an equivalent amount of a partially reducedheteroaromatic compound having an activated C=N function of Formula IIIuntil no compound of the Formula IV is detectable in the vapors by odoror pH measurements. Compound IV is a by-product of the main reaction. Atthis point the solvent is removed under reduced pressure and the residuerecrystallized. Other suitable solvents for this reaction are:tetrahydrofuran, toluene, xylene and the like.

The starting phenolic Mannich bases II are prepared according to themethods described in a-Aminoalkylie rung by H. Hellmann and G. Opitz,Verlag Chemie G.M.B.H. Weinheim, Germany 1960 or by the methodsdisclosed in J. Org. Chem, 27, p. 1211, January 1962. Some startingcompounds of Type II such as l-dimethylamino-2-naphtho1 are availablefrom Aldrich Chem. Co. A suitable general procedure for the preparationof phenolic Mannich bases of type II is as follows: A solu tion of 0.1mole of the appropriate phenol, 5.4 g. of dimethylamine and 8.5 ml. of37% formaldehyde in 200 ml. ethanol is refluxed for 5 hours and allowedto stand overnight at 0 to 5 C. The precipitate formed is removed byfiltration and recrystallized from anhydrous ethanol.

Starting materials of type III were prepared by known literatureprocedures described, for example, by R. C. Elderfield in HeterocyclicCompounds, vol. 4, p. 349, John Wiley and Sons, Inc., New York, 1952.Starting materials of type III can also be prepared according to themethods described by Whaley et al. in Organic Reactions, vol. VI,Chapter 2, particularly pages 104 and 142.

3,4-dihydro-fi-carboline is described by Schopf et al., in Ann. 558: 124(1947); 6,7-dimethoxy-3,4-dihydroisoquinoline by Haworth, in J. Chem.Soc., (1927) 2281; 6- methoxy-3,4-dihydroisoquinoline by Gulland andVinde'n, J. Chem. Soc., (1929) 1791;3-carbethoxy-4-dimethylamino-methyl-S-hydroxy-Z-methylindole by Bell etal., I. of Med. Chem, vol. 10, 264 (1967); and6-dimethylaminoethyl-Z-rnethoxyphenol by Eliel, J. Amer. Chem. S'oc.,73, 43 (1951). 1(2H)-phthalazinone is also available from Aldrich Chem.Co.

In general, compounds of type III are prepared by theBischler-Napieralski cyclization of the corresponding N- formylaralkylamine which involves refluxing the latter in toluene or xylene inthe presence of a dehydrating agent such as P or POCl The compounds ofour invention may 'be converted into their pharmaceutically acceptablenontoxic acid addition and quaternary ammonium salts by conventionalprocedures. Exemplary of nontoxic acid addition salts are those formedwith acetic, maleic fumaric, succinic, tartaric, citric, malic,cinnamic, sulfonc, hydrochloric, hydrobromic, sulfuric, phosphoric andnitric acids. The acid addition salts may be prepared in theconventional manner by treating a solution or suspension of the freebase in an organic solvent with the desired acid, and then recoveringthe salts which form by crystallization techniques. The quaternary saltsare prepared by heating a suspension of the free base in a solvent witha reactive halide such as methyl iodide, ethyl bromide, n-hexyl bromide,benzyl chloride or a reactive ester such as methyl sulfate, ethylsulfate or methyl p-tolune sulfonate.

The following examples are included in order further to illustrate theinvention.

EXAMPLE 1 GHSOO/W onso N l T A 12,13-dihydro-9,10-dimeth0xy-7aI-I,15H-benz[f] isoquino[1,2-b][1,3]benzoxazine A solution of 3.82 g. of3,4dihydro-6,7-dimethoxy-isoquinoline, and 4 g. of1-dimethylarninomethyl-Z-naphthol in 20 ml. of dioxane was refluxedunder a stream of nitrogen for 3 hr. The solution was cooled, and thecrystalline precipitate was filtered, washed with cold dioxane, andrecrystallized from CH CN M.P. 185-187"; yield 2.5 g. (36%); A mu. (6)229 (97,000); 277 (12,700), 310 (7,600); 11 755 (m.), 825 (ms), 860(ms.), 975 (mw.), 1015 (m.), 1100 (ms), 1125 (s.), 1225 (s.), 1265(ms.), 1515 (m.), 1600 (m.), 1625 (mw.) cmf Analysis.Calcd. for C -H NO(percent): C, 76.06; H, 6.09; N, 4.03. Found (percent): C, 76.13; H,6.02; N, 4.15.

EXAMPLE 2 crno q 30 5,6-dihydro-2, 3,l2-trimethoxy-8H,13aH-isoquino1,2-b] [1,3 ]benzoxazine reduced pressure, and the residual oil wasrecrystallized from ethylacetate; M.P. 152-164"; yield 3.5 g. (20%); 71mu (e) 237 (35,600), 281 (6,800), 310 (1,680), 324 (1,640); v 725 (mw.),810 (mw.), 960 (mw.), 1070 (m.), 1115 (m.), 1160 (ms), 1225 (ms), 1250(s.), 1510 (m.), 1590 (mw.), 1610 (mw.), cmr

Analysis.--Calcd. for C H NO (percent): C, 69.70; H, 6.47; N, 4.28.Found (percent): C, 69.63; H, 6.57; N, 4.36.

EXAMPLE 3 CH... W 011 0 \T3-bromo-l2,13-dihydro-9,10-dimethoxy-7aH,1SH-benz [f] isoquino [-1,2b]1,3 ]benzoxazine This was prepared from 3.82 g. of3,4-dihydro-6,7-dimethoxyisoquinoline, and 5.6 g. of6-bromo-1-dimethylaminomethyl-2-naphthol in analogous fashion to 12,13-dihydro 9,10-dirnethoxy-7aH,l5H- benz[f]isoquino[1,2-b][1,3]benzoxazine. Recrystallized from CH CN, M.P. 200-201; yield 3 g.(35%); x m,u (e) 234 (100,000), 270 (11,600), 278 (13,200), 310 (7,300);v 740 (mw.), 805 (m.), 830 (ms), 945 (m.), 1010 (mw.), (m.), 1120(1115.), 1220 (s.), 1265 (ms), 1520 (m.), 1590 (m.), 1615 (m.),cmf

Analysin-Calcd. for C H BrNO (percent): C, 61.98; H, 4.73; N, 3.29.Found (percent): C, 62.25; H, 5.01; N, 3.54.

EXAMPLE 4 This was prepared from 6.8 g. of 3,4 dihydro-fi-carboline, and10 g. of 1-dimethylaminomethyI-Z-naphthol in analogous fashion to12,13-dihydro-9,10-dimethoxy-7aH,15H-benz[f]isoquino[1,2-b][1,3]ben2oxa2ine. The product wasrecrystallized from ethanol-tetrahydrofuran, M.P. 2005-2025; yield 4.3g. (26%); x mu (e) 229 85,- 900), 265 (6,800), 278 (8,400), 289 (9,100),319 (15,- 300); v 740 (ms.), 800 (m.), 890 (ms), 935 (mw.), 1010 (mw.),1110 (m.), 1220 (s.), 1600 (m.), 1625 (m.), 3390 (ms), crnfAnalysis.Calcd. for C H N O (percent): C, 80.95; $1485.56; N, 8.58.Found (percent): C, 80.83; H, 5.55; N,

EXAMPLE 5 A solution of 2.92 g. of 1(2H)-phtha1azinone and 4 g. of1-dimethylaminomethyl-Z-naphthol in 20 ml. of dioxane was refluxed undera stream of nitrogen for 18 hrs. and cooled. The crystalline precipitatewas filtered, and recrystallized from abs. ethanol M.P. 183-1855; yield3 g. (50%); A m (6) 211 (56,000), 227 (72,400), 279 (10,200), 288(10,000); A 680' (m), 750 (m), 725 (ms), 900 (In), 1005 (mw), 1155 (mw),1235 (ms), 1585 (ms), 1605 (In), 1635 (s), 3075 (m) cm.-

Analysis.-Calcd. for C H N O (percent): C, 75.48; H, 4.67; N, 9.27.Found (percent): C, 75.34; H, 4.64; N, 9.49.

EXAMPLE 6 CHaO CHQO W 12.l3-dihydro-9,10-dimethoxy-7al-I,l5H-quino-[5,6' 5,6] [1,3]oxazino[2,3-a] isoquinoline A solution of 7.5 g. ofS-dimethylaminomethyl-6-quinolinol, and 7.1 g. of3,4-dihydro-6,7-dimeth0xyisoquinoline in 75 ml. of dioxane was refluxedunder a stream of nitrogen for 4 hr. The solution was filtered free of asmall amount of insoluble material, and the filtrate was taken down to agum under reduced pressure. The gum was recrystallized from abs.ethanol, M.P. 175-177; yield 2 g. A ma (6) 233 (50,400), 282 (10,000),313 (7,500); X 790 (m.), 825 (ms.), 950 (mw.), 1010 (mw.), 1100 (ms.),1130 (ms.), 1215 (s.), 1260 (m.), 1500 (m.), 1515 (m.), 1610 (m.) cm.-

Analysis.Calcd. for C H N O (percent): C, 72.39; H, 5.79; N, 8.04. Found(percent): C, 72.62; H, 5.74; N, 8.32.

EXAMPLE 7 2-brorno-7,8,1,3,13b-tetrahydro-5H-naphth[1",2":5',6-'] [1,3oxazino[3',2: 1,2] pyrido [3 ,4-b] indole This was prepared from 3.4 g.of 3,4-dihydro-fl-carboline, and 5.6 g. of6-bromo-l-dimethylaminomethyl-Z- naphthol in analogous fashion to7,8,13,13b-tetrahydro- 5Hnaphth[1",2":5',6'][1,3]oxazin0[3',2':1,2]pyrido- [3,4-b]indole. Thematerial was recrystallized from pyridine, M.P. 209-2l1; yield 2 g.(25%); A mu (e) 235 (74,000), 267 (5,500), 279 6,700), 290 (7,100), 319(12,800); k 735 (ms.), 800 (m.), 860 (ms.), 930 (m.), 985 (m.), 1010(m.), 1060 (m.), 1120 (m.), 1220 (s.), 1590 (m.), 1615 (m.), 3400 (ms.)cmr Analysis.--Calcd. for C H BrN O (percent): C, 65.20; H, 4.23; N,6.91. Found (percent): C, 65.31; H, 4.43; N, 6.76.

EXAMPLE 8 12, 13-dihydro-9-methoxy-7aH, ISH-benz [f] isoquino[ 1,2-b]1,3 ]benzoxazine A solution of 3.22 g. of3,4-dihydro-6-methoxyisoquinoline, and 4.02 g. of1-dimethylaminomethyl-Z-naphthol in 20 ml. of dioxane was refluxed undera stream of nitrogen for 3 hr. The mixture was chilled, and thecrystalline precipitate was filtered, and recrystallized from toluene,M.P. 191-193; yield 2 g. (31%); A m (e), 228 (83,400); 277 (19,100); A765 (mw.), 815 (ms.), 855 (ms.), 940 (m.), 1030 (m.), 1125 (ms.), 1215(s), 1260 (ms.), 1510 (m.), 1590 (m.), 1610 (m.), 1620 (m.) cmrAnalysis.C'alcd. for C H NO (percent): C, 79.47; H, 6.03; N, 4.41. Found(percent): C, 79.53; H, 6.03; N, 414.

EXAMPLE 9 Ethyl 3,1 1,12,14-tetrahydro-9-methoxy-2-methyl6aH-indolo[4,5:5,6]oxazino[2,3-a]isoquinoline 1 carboxylate C 11 CH;

A solution of 3.32 g. of 3,4-dihydro-6-methoxyisoquinoline, and 5.5 g.of ethyl 4-[(dimethylamino)methyl]-5-hydroxy-Z-methylindolo-3-carboxy1ate in 20 ml. of dioxane was refluxedunder a stream of nitrogen for 3 hrs. The dioxane was removed underreduced pressure, and the residue was recrystallized from ethyl acetate,M.P. 190.5191.5; yield 4.2 g. (54%); r m (e) 220 (39,200); 253 (21,500);m 730 (mw.), 920 (m.), 1065 (ms.), 1085 (ms.), 1150 (ms.), 1230 (s.),1585 (m.), 1610 (m.), 1695 (ms.) cm.-

Analysis.-Calcd. for C H N O (percent): C, 70.39; H, 6.16; N, 7.14.Found (percent): C, 70.28; H, 6.28; N, 7.05.

It is understood that the foregoing detailed description is given merelyby way of illustration and that many variations may be made thereinwithout departing from the spirit of our invention.

Having described our invention, what we desire to secure by LettersPatent is:

1. A member selected from the group consisting of a free base of theformula:

R Blob 2 X represents 1,2,3,4-tetrahydroisoquinoline,l,2,3,4-tetrahydr-2-carboline and tetrahydro-4 phthalazinone; Z isbenzene, naphthalene, quinoline in which the quinoline is attached asfollows:

and indole in which the indole is attached as follows:

and when Z is quinoline or indole X is 1,2,3,4-tetrahydroisoquinolineand when X is 1,2,3,4-tetrahydro-2-carbo1ine ortetrahydro-4-phthalazinone Z is naphthalene, R and R are hydrogen, loweralkyl, lower alkoxy, halogen, carbo lower alkoxy; and R is hydrogen orits nontoxic pharmaceutically acceptable acid addition salts.

2. 12,13 dihydro 9,10 dimethoxy 7aH,l5H-benz [f]isoquino[1,2 b][1,3]benzoxazine or its nontoxic pharmaceutically acceptable acidaddition salts.

3. 5,6 dihydro 2,3,12 trirnethoxy 8H,13aH isoquino[1,2-b][1,31benzoxazine or its nontoxic pharmaceutically acceptable acidaddition salts.

4. 3 bromo 12,13 dihydro 9,10 dimethoxy 7aH, 15Hbenz[f]isoquino[1,2-b][1,3]bcnzoxazine and its nontoxic pharmaceuticallyacceptable acid addition salts.

5. 7,8,13,13b tetrahydro 5H naphth[1",2":5,6'][l,3]oxazine[3,2:1,2]pyrido[3,4-b]indole or its nontoxicpharmaceutically acceptable acid addition salts.

6. 5,15a dihydro 6H,8H naphth[1',2':5,6]oxazino [2,3-a[phthalazin 5 oneor its nontoxic pharmacetutically acceptable acid addition salts.

7. 12,13 dihydro 9,10 dimethoxy 7aH,15H-quino [5,6:5,6][1,3]oxazino[2,3-a]isoquinoline or its nontoxic pharmaceuticallyacceptable acid addition salts.

8. 2 bromo 7,8,13,13b tetrahydro 5H naphth[1",2":5,6][1,3]oxazino[3',2:1,2]pyrido[3,4 b]indole or its nontoxicpharmaceutically acceptable acid addition salts.

9. 12,13 dihydro 9 methoxy 7aH,15H benz[f]isoquino[2,2-b][1,3]benzoxazine or its nontoxic pharmaceuticallyacceptable acid addition salts.

10. Ethyl 3,11,12,14 tetrahydro 9 methoxy 2- methyl 6aH indole[4',5:5,6]oxazino[2,3 a]isoquinoline-l-carboxylate or its nontoxicpharmaceutically acceptable acid addition salts.

11. Process for the preparation of a free base of claim 1 whichcomprises containing a compound of the Formula II wherein R and R arelower alkyl or lower alkyl phenyl, or R, and R taken together with thenitrogen atom to which they are attached form a morpholine, pyrrolidine,piperazine or piperidine ring, is heated in an enert solvent with anequivalent amount of a partially reduced heteroaromatic compound havingan activated C=N function of Formula III until no compound of theFormula IV is detectable.

References Cited UNITED STATES PATENTS 10/ 1961 Van Campen et a1. 260244R OTHER REFERENCES NATALIE TROUSOF, Primary Examiner U.S. Cl. X.R.

260-247.2 R, 247.2 A, 247.2 B, 247.5 R, 247.5 B, 247.7 A, 250 A, 251 Q,251 R, 256.4 C, 256.4 H, 268 TR, 268 BC, 268 HQ, 268 H, 268 R, 283 R,287 R, 288 R, 289 R, 293.59, 293.61, 293.65, 295 C, 296 A, 326.3, 326.5L, 326.5 N; 424-248

